Preparation method of alarelin

A kind of technology of alanorelin and alanorelin is applied in the preparation method of peptide, chemical instrument and method, organic chemistry and other directions, and can solve the problems such as the preparation method of alanorelin that has not been disclosed.

Active Publication Date: 2017-12-08
上海丽珠制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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  • Preparation method of alarelin
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  • Preparation method of alarelin

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Activate Boc-Pro

[0028] Weigh 193.8g of Boc-Pro in a three-necked flask and dissolve it in 1200ml of methanol.

[0029] Weigh 190.6g of Cs in the three-necked flask 2 CO 3 Soluble in 1200mlH 2 O was slowly added to the above Boc-Pro solution to obtain a colorless and transparent Boc-Pro-Cs solution with a pH value of 7.2.

[0030] Concentrate under reduced pressure with a water pump in a water bath at 40°C, evaporate the solvent to obtain a solid; add 500ml of methanol, evaporate to dryness under reduced pressure, add 500ml of methanol again and evaporate to dryness under reduced pressure to obtain 400g of dry Boc-Pro-Cs.

Embodiment 2

[0032] Boc-Pro curing

[0033] Boc-Pro-Cs was prepared according to the method described in Example 1.

[0034] Weigh 670g of chloromethyl resin, 400g of Boc-Pro-Cs and 2000ml of DMF, dissolve them completely and pour them into a three-neck flask.

[0035] Stir and react in a water bath at 45°C for 48 hours, filter with suction, wash the resin 3 times with DMF, then wash with purified water until no Cl- reaction occurs, wash 4 times with absolute ethanol, and wash 2 times with methanol. Dry in an oven at 40-45°C to obtain dried Boc-Pro resin.

[0036] The substitution equivalent number of Boc-Pro is 0.92mmol / g, and the reaction yield is 96%.

Embodiment 3

[0038] Boc-Pro curing

[0039] Boc-Pro-Cs was prepared according to the method described in Example 1.

[0040] Weigh 670g of chloromethyl resin, 300g of Boc-Pro-Cs and 1800ml of DMF, and pour them into a three-necked flask after completely dissolving.

[0041] Stir and react in a water bath at 45°C for 48 hours, filter with suction, wash the resin 3 times with DMF, then wash with purified water until no Cl- reaction occurs, wash 4 times with absolute ethanol, and wash 2 times with methanol. Dry in an oven at 40-45°C to obtain dried Boc-Pro resin.

[0042] The substitution equivalent number of Boc-Pro was 1.0 mmol / g, and the reaction yield was 97%.

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Abstract

The invention provides a preparation method of alarelin. The method comprises the following steps: (1) activating Boc-Pro: respectively dissolving Boc-Pro and Cs2CO3, mixing the Boc-Pro and the Cs2CO3, and preparing an activated Boc-Pro product Boc-Pro-Cs; (2) curing Boc-Pro: dissolving the Boc-Pro-Cs and a merrifield resin, curing the Boc-Pro, and preparing a Boc-Pro resin; (3) grafting a peptide: sequentially connecting the Boc-Pro resin with Boc-Arg, Boc-Leu, Boc-Ala, Boc-Tyr, Boc-Ser-(But), Boc-Trp, Boc-His-(Tos), pGlu through a one-by-one coupling mode, and synthesizing to obtain an alarelin-resin; (4) conducting aminolysis on the alarelin-resin to remove the resin, transforming into acetate, and obtaining a crude product of alarelin; (5) purifying the crude product of alarelin through HPLC (High Performance Liquid Chromatography), and freeze-drying to obtain a finished product of alarelin. Through the method, the alarelin with high yield and purity is obtained, the reaction is simple and controllable, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a preparation method of amolide. Background technique [0002] Alanorelin is a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) developed by my country. It can stimulate the pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH) at the initial stage of medication, causing ovarian-derived steroid hormones. Short-term increase in hormones; repeated medication can inhibit the release of LH and FSH from the pituitary gland, reduce the level of estradiol in the blood, and achieve the effect of drug ovariectomy. This inhibitory effect can be used to treat hormone-dependent diseases such as endometriosis . Existing information has not disclosed the preparation method of acerelin. Contents of the invention [0003] The object of the present invention provides a kind of solid-phase preparation method of acerelin, this method can obtain t...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/04C07K1/06C07K1/16C07K1/14
CPCC07K7/23
Inventor 万龙岩王林鹏施海蓉张道桂张天骄何免免向双
Owner 上海丽珠制药有限公司
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